The adenosine A2A receptor (A2AR) has emerged as a promising target for Parkinson's disease (PD) therapy based on its ability to modulate dopaminergic neurotransmission and its remarkably discrete localization to a subset of striatal output neurons. Preclinical evidence that A2A antagonists reliably reduce motor disability without producing dyskinesias (motor complications of standard L-dopa therapy) in parkinsonian primates has led to encouraging initial clinical data on A2A antagonists in advanced PD patients already experiencing dyskinesias. However, little is known about the role of A2ARs in the maladaptive neuroplasticity underlying the development of L-dopa-induced dyskinesias (LID). We and others have demonstrated that A2AR inactivation can prevent or reverse sensitized motor responses to repeated L- dopa administration in rodent and primate models of dyskinesias. Here in response to NIH PAS-02-129 we propose to systematically investigate A2AR involvement in the maladaptive neuroplasticity of a mouse model of LID. Using complementary genetic (constitutive and brain-specific conditional knockout) and classical pharmacological approaches to adenosine (At and A2A) receptor inactivation, we will systematically pursue 3 specific aims: 1) To determine the adenosinergic (A1 and A2A) contributions to L-dopa sensitization in hemiparkinsonian (6-OHDA-lesioned) mice. 2) To determine whether A2A antagonists reduce L-dopa- induced behavioral sensitization by preventing its induction, maintenance and/or expression. 3) To explore how the A2AR interacts with its dopaminergic and heteromeric GPCR partners (D1, D2 and mGluS receptors) in modulating L-dopa sensitization. We will also assess the role of adenosine receptors in molecular adaptations linked to dyskinesias, including changes in striatal expression of dynorphin, enkephalin and the A2AR itself. Relevance: In addition to providing fundamental insights into adenosine neurobiology, the proposal is designed to yield practical knowledge of adenosine receptor function in a model of the dyskinesias that complicate standard antiparkinsonian treatments. The translational potential and efficiency of the project will be further enhanced by coordinating its ongoing findings with parallel non-human primate and clinical programs currently pursuing the therapeutic benefits of A2A antagonists for PD. [unreadable] [unreadable] [unreadable]